CN101623286B - Transdermal administration composite containing cucurbitacin-type active ingredient - Google Patents
Transdermal administration composite containing cucurbitacin-type active ingredient Download PDFInfo
- Publication number
- CN101623286B CN101623286B CN200910012907.9A CN200910012907A CN101623286B CN 101623286 B CN101623286 B CN 101623286B CN 200910012907 A CN200910012907 A CN 200910012907A CN 101623286 B CN101623286 B CN 101623286B
- Authority
- CN
- China
- Prior art keywords
- cucurbitacin
- transdermal
- skin
- gel
- percutaneous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000004480 active ingredient Substances 0.000 title claims abstract description 42
- 239000002131 composite material Substances 0.000 title description 12
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- 239000000499 gel Substances 0.000 claims abstract description 57
- 238000002360 preparation method Methods 0.000 claims abstract description 32
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- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 26
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Abstract
本发明涉及一种包含葫芦素类活性成分的经皮给药组合物。葫芦素类活性成分的经皮给药制剂中的经皮通透促进剂为油酸、氮酮、桉油、或肉豆蔻酸异丙酯等中的一种或多种的组合物，经皮通透促进剂的用量为0.1～50％，最好为0.3～30％。葫芦素类活性成分的经皮给药可以采用凝胶剂、乳剂、软膏剂、溶液剂、微乳剂、醇质体或喷雾剂等液体和半固体制剂，或贴剂、巴布剂等贴膏剂。上述制剂经皮给药后，活性成分可长时间持续通过皮肤吸收进入体内发挥治疗作用，患者适应性显著优于口服用药，可用于肝炎、癌症等疾病的预防、治疗和改善患者生活质量。The invention relates to a transdermal administration composition containing cucurbitacin active ingredients. The transdermal permeation enhancer in the transdermal preparation of cucurbitacin active ingredients is a composition of one or more of oleic acid, azone, eucalyptus oil, or isopropyl myristate, etc., transdermal The dosage of the penetration enhancer is 0.1-50%, preferably 0.3-30%. The transdermal administration of cucurbitacin active ingredients can adopt liquid and semi-solid preparations such as gels, emulsions, ointments, solutions, microemulsions, ethanols or sprays, or plasters such as patches and cataplasms . After the above preparation is administered through the skin, the active ingredients can be continuously absorbed through the skin into the body for a long time to play a therapeutic role, and the patient adaptability is significantly better than that of oral administration. It can be used for the prevention and treatment of hepatitis, cancer and other diseases and improve the quality of life of patients.
Description
Technical field
The present invention relates to medical technical field, relate to the transdermal administration composite that comprises cucurbitacin-type active ingredient, especially relate to a kind of for preventing or treat the transdermal administration composite of hepatitis or cancer.
Background technology
Bibliographical information, cucurbitacine composition has multiple therapeutic activity, wherein multiple components have cytotoxicity, hepatoprotective effect, antiinflammatory action, Cardiovascular and antidiabetic effect are (referring to Jayaprakasam B, et al., Anticancer and anti-inflammatory activities of cucurbitacins from Cucurbitaandreana.Cancer Lett, 2003, 189:11-16. and Yesilada E, et al., Isolation of ananti-inflammatory principle from the fruit juice of Ecballium elaterium.J NatProd, 1988, 51:504-508.).In recent years, studies have reported that confirmation: Cucurbitacin B, D, E and I can suppress the growth of some JEG-3, and suppress cyclooxygenase 2 but not Cycloxygenase 1, Cucurbitacin B and I also show obvious inhibitory action to melanoma cell, the glucoside of Cucurbitacin B and E can play effective chemoprophylaxis effect to human breast carcinoma, dihydro Cucurbitacin B can suppress human breast cancer cell strain Bcap37, HeLa, SW620, SMMC-7721, K562 and MCF-7 hypertrophy, can induce human breast cancer cell Bcap37 apoptosis in the time of very low concentrations, Cucurbitacin B, to the neurilemmal hypertrophy of human breast cancer cell ER, Her2 and p53 mutant, all shows obvious anti-Reproductive activity, Cucurbitacin B, E have stronger lethal effect to nasopharyngeal carcinoma cell, can promote normal lymphocytic transformation function simultaneously, Cucurbitacin B can be induced the differentiation of cellulous leukemia of bone marrow cell effectively, cell cycle arrest and actin cytoskeleton rotten (Yang Kai. the acute toxicity of CucurbitacinBE Polylactic Acid Nano-particles of Targeting Cervical Lymph Nodes and the research of local stimulation test. West China Journal of Stomatology, 2001, 19 (6): 380-382.Peters RR, et al.Anti-inflammatory effects ofthe products from Wilbrandia ebracteata on carrageenan-induced pleurisy inmice.Life Sci, 1999, 64:2429-37.Yang L, et al.23, 24-Dihydrocucurbitacin Binduces g2/M cell-cycle arrest and mitochondria-dependent apoptosis in humanbreast cancer cells (Bcap37) .Cancer Lett, 2007, 256 (2): 267-278.Haritunians T, etal.Cucurbitacin B induces differentiation, cell cycle arrest, and actin cytoskeletalalterations in myeloid leukemia cells.Leukemia Res, 2008, 32 (9): 1366-1373.).Cucurbitacin-type active ingredient is having potential applicability in clinical practice widely aspect the treatment of hepatitis, kinds of tumors disease etc.
At present, comprise tablet, drop pill and the soft gelatin capsule of oral administration administration in the dosage form using cucurbitacine material as active component of development, and injection and the liposome etc. of administrated by injection (Shi Hanhua. the pharmacological evaluation of muskmelon pedicel injection. Journal of Chinese Hospital Pharmacy, 1985,5 (7): 27; Zhang Xiaoxiang, Su Desen. the preparation of Cucurbitacine liposome and property research. Chinese herbal medicine, 1991,22 (2): 62. is husky quiet pretty, Mao Hongkui. cucurbitacin sheet. pharmacy circular, 1986,21 (6): 357.); Wherein gone on the market and only had cucurbitacin sheet for clinical product, its main active is Cucurbitacin B and cucurbatacin E, clinical chronic hepatitis, chronic persistent hepatitis and the primary hepatocarcinoma of being used for the treatment of.
Although existing cucurbitacin tablet has been brought into play the therapeutic activity of cucurbitacin-type active ingredient to a certain extent, for hepatitis or cancer patient have brought the improvement of more chance for survival or quality of life, but the application of cucurbitacin tablet exists many-sided limitation, be summarised as following several aspect: 1. administration volume is large, have any problem or detest poor compliance for the crowd of oral administration for swallowing; 2. there is first pass effect, be easily eliminated in vivo, thereby increased dosage and increased gastrointestinal side effect; 3. can not give effective blood drug level to body with administration concentration stably, thereby therapeutic effect is poor, and needs frequent drug administration.Therefore, be currently extremely necessary to find a kind of new form of administration and overcome above-mentioned defect, to obtain better therapeutic effect.
Percutaneous dosing is a kind of newtype drug delivering method, and it not only can bring into play local therapeutic effects, as alleviated the position pain such as muscle and joint etc., and can make the active substance of effective dose enter body circulation, realizes whole body therapeutic effect.The advantage of percutaneous dosing is the safety that can reduce blood concentration fluctuation, reduce medicine toxicity, be convenient to stop at any time administration, improve medication; Avoid gastrointestinal tract and liver first pass metabolism; Extend action time, reduce medication number of times; Easy to use, be easy to be accepted by old people and patient that should not be oral and some especial patient; Improve the compliance of patient's medication.
But; not active substance is all applicable to for being prepared into percutaneous drug administration preparation arbitrarily; because normal person's skin is as the outermost layer tissue of human body; there is protection body and exempt from the function that the various harmful substances of external environment are invaded; this function has caused the malabsorption of skin to medicine, and this skin malabsorption and medicine all can affect the effective blood drug concentration that enters body circulation to the distribution of skin lower floor.In addition the dosage of medicine and concentration, molecular size and fat-soluble, pH and pK,
adeng also active substance can being made to percutaneous drug administration preparation and has been proposed challenge.
Applicant finds under study for action unexpectedly, cucurbitacin active substance in the present invention has good stability to skin enzyme system, particularly Cucurbitacin B, its metabolite is mainly the cucurbitacin D with similar activity, and the percutaneous transmission that this is cucurbitacin-type active ingredient provides feasibility; And, transdermal administration composite of the present invention is applied to after patient skin, active component can continue to absorb to enter in body, to bring into play therapeutical effect by skin for a long time, the pharmacokinetics process of itself and continuous infusion low concentration natural antitumor medicine is similar, thereby the drug resistance that is expected to reduce tumor cell further improves therapeutic effect.
Summary of the invention
In order to overcome the relevant applied defect of cucurbitacin sheet in prior art, acquisition compliance is better, administration number of times is few, side effect is little and release curve form of medication more stably, the invention provides a kind of transdermal administration composite, its technical scheme by following description realizes.
On the one hand, the invention provides a kind of transdermal administration composite, it is characterized in that comprising the penetrating promoter of cucurbitacin-type active ingredient and percutaneous, wherein said cucurbitacin-type active ingredient is selected from one or more in Cucurbitacin B, cucurbitacin D, cucurbatacin E, cucurbitacin H, cucurbitacin I, cucurbitacin K and cucurbitacin Q, and the penetrating promoter of described percutaneous is selected from one or more in oleic acid, azone, Oleum Eucalypti, isopropyl myristate, N-Methyl pyrrolidone, Mentholum, Borneolum Syntheticum, diethylene glycol monoethyl ether, ethanol and propylene glycol.
Cucurbitacin-type active ingredient in the present invention comprises: one or more in Cucurbitacin B, cucurbitacin D, cucurbatacin E, cucurbitacin H, cucurbitacin I, cucurbitacin K and cucurbitacin Q.The chemical constitution of these active component is similar, molecular weight is close, and therefore transdermal character is also more approaching.It will be understood by those skilled in the art that one or more the combination in any in above-mentioned active component is all applicable to transdermal administration composite of the present invention.Cucurbitacin-type active ingredient of the present invention is through extraction, purification process, and the purity of effective monomer is high, preferably adopts the more than 95% cucurbitacine effective monomer of purity, and lower like this dosage can reach effective therapeutical effect.
Due to the barrier action of human body skin, most drug percutaneous permeabilitys are very low, in order to improve the penetrating amount of percutaneous of active component, guarantee that the dosage transdermal that enough produces drug action enters in human body, can adopt the penetrating promotion method of multiple percutaneous, comprise method and the chemical method of physics.Chemical method is exactly to utilize the penetrating short agent of suitable chemical percutaneous to improve the penetrating amount of percutaneous of active component.The present invention finds under study for action, and one or more that use oleic acid, azone, Oleum Eucalypti, isopropyl myristate, Borneolum Syntheticum, Mentholum etc. can effectively promote cucurbitacin-type active ingredient infiltration to pass through skin.Although ethanol and propylene glycol also have the effect that promotes that drug percutaneous sees through, but compare with penetrating promoter as solvent with simple ethanol and/or the propylene glycol used, while adopting the above-mentioned penetrating promoter of percutaneous, the penetrating short property of the percutaneous of cucurbitacin-type active ingredient can significantly increase.
Wherein, the preferred penetrating promoter of percutaneous is one or more in oleic acid, azone, Oleum Eucalypti and isopropyl myristate.
In preparation, the consumption of the penetrating promoter of percutaneous is the key factor that determines percutaneous drug absorption amount, and along with the consumption of the penetrating promoter of percutaneous increases, and the transit dose of medicine might not monotone increasing, but may have best consumption.For azone and oleic acid etc., the transit dose maximum of consumption medicine in the time of 1% left and right; And isopropyl myristate and Oleum Eucalypti etc., in certain amount ranges, the transit dose of medicine increases monotone increasing with its consumption.The factor that another one need to be considered is that the consumption of the penetrating promoter of percutaneous too much may produce the untoward reaction such as skin irritation.In transdermal administration composite of the present invention, the percentage by weight of the penetrating promoter of percutaneous is 0.1-50%, and in preferred composition, the percentage by weight of the penetrating promoter of percutaneous is 0.3-30%.
The dosage form of the transdermal administration composite described in the present invention can be gel, Emulsion, ointment, solution, microemulsion, ethosome or spray, patch or cataplasma.According to the feature of every kind of preparation, need to adopt known pharmaceutical preparation technology preparation, wherein the preparation of spray can be that above-mentioned gel, solution, microemulsion or ethosome are packed in suitable medicinal automiser spray and made.
According to the feature of preparation, the amount of the cucurbitacin-type active ingredient wherein containing is as follows: in gel, Emulsion, ointment, solution, microemulsion, ethosome or spray, the weight percentage of cucurbitacin-type active ingredient is 0.01%-10%, is preferably 0.05%-2.5%; In the every subsides of patch and cataplasma, the content of cucurbitacin-type active ingredient is 0.1 milligram-100 milligrams, is preferably 0.5 milligram-25 milligrams.
In order to prepare safe, effective, quality controllable percutaneous drug administration preparation, can in transdermal administration composite of the present invention, add other pharmaceutic adjuvant well known in the art, such as pressure sensitive adhesive, gel-type vehicle, solvent, antiseptic and/or stabilizing agent etc.
In cucurbitacin-type active ingredient, Cucurbitacin B and cucurbatacin E, especially Cucurbitacin B is the higher composition of content in medical material, Cucurbitacin B has obvious curative effects for prevention and treatment cancer, hepatitis, in research of the present invention, find, Cucurbitacin B also has similar pharmacologically active through the primary product cucurbitacin D of skin enzyme or other effect degradeds.Deacetylation by Cucurbitacin B can be prepared cucurbitacin D easily in a large number.
Therefore, in another aspect of this invention, provide the application of the medicine of transdermal administration composite of the present invention in preparation treatment hepatitis or cancer.
Percutaneous drug administration preparation described in the invention, after skin single-dose, active component can continue more than 24 hours to be absorbed and entered human body performance therapeutical effect by skin, and to skin nonirritant, patient's compliance is good.
Accompanying drawing explanation
Fig. 1 is for the horizontal diffusion cell of in-vitro percutaneous permeability research and the schematic diagram of vertical (Franz) diffusion cell.
(A) being horizontal diffusion cell, is (B) vertical (Franz) diffusion cell
Fig. 2 is with after the penetrating promoter pretreatment of different percutaneous isolated rat skin of abdomen, accumulation transit dose (Q)～time (t) curve of Cucurbitacin B saturated solution Chinese medicine.
Fig. 3 is that Cucurbitacin B gel is through accumulation medicine transit dose (the Q)～time of different animals, different parts isolated skin (t) curve.
Fig. 4 is through accumulation medicine transit dose (the Q)～time of skin of rat (t) curve containing the Cucurbitacin B gel of the penetrating promoter oleic acid of different amounts percutaneous and the Cucurbitacin B gel that do not contain the penetrating promoter oleic acid of percutaneous.
The specific embodiment
The present invention will carry out more detailed explanation below contrasting specific embodiment, but it is restricted to it will be appreciated by persons skilled in the art that these specific embodiments do not have.
embodiment 1: the research method of the in-vitro percutaneous permeability of cucurbitacin-type active ingredient.
With the penetrating promoter pretreatment of different percutaneous animal isolated skin, medicine is seen through to sex experimental technique as follows: experiment equipment therefor is horizontal diffusion cell, as shown in Figure 1.Get healthy male Wistar rat, after anesthesia, cut off the Mus hair on skin of abdomen, after carefully pruning with shaver, peel off skin, be laid in smooth plates, horny layer is downward, reject subcutaneous fat and be adhered thing, after repeatedly rinsing well with normal saline, being cut into suitable size, freezing for subsequent use, before experiment, the integrity of visual inspection Corium Mus, must not have any breakage.Getting Corium Mus for subsequent use thaws naturally, be sandwiched between two and half ponds of diffusion cell, horny layer is towards administration pond, in administration pond, add the alcoholic solution of 5% penetrating promoter, in reception tank, add 40% propylene glycol solution, sealing, places 8 hours under 32 ℃ of conditions, solution in diffusion cell is inclined to, repeatedly rinse with distilled water and 40% propylene glycol solution successively; Then in administration pond, add Cucurbitacin B saturated solution (with 40% propylene glycol solution be solvent) 3.5 milliliters, in reception tank, add 3.5 milliliter of 40% propylene glycol solution as receiver media, 32 ℃ of temperature constant magnetic stirrings, sample at different time interval respectively, add isopyknic 40% propylene glycol solution simultaneously, sample filters through microporous filter membrane, and the content of high effective liquid chromatography for measuring Cucurbitacin B is drawn drug accumulation and seen through curve.
Medicine containing the preparation of cucurbitacin-type active ingredient is as follows through the permeability experimental technique of Animal skin: experiment equipment therefor is vertical (Franz) diffusion cell, as shown in Figure 1.Get the Animal skin of processing and naturally thawing as stated above, be sandwiched between two and half ponds of vertical diffusion cell, keratodermatitis is towards supply pool, investigated preparation is placed in to supply pool, in acceptance pool, add 40% propylene glycol solution as receiver media, 32 ℃ of temperature constant magnetic stirrings, sample at different time interval respectively, sample filters through microporous filter membrane, the content of high effective liquid chromatography for measuring cucurbitacin-type active ingredient, the accumulation of drawing medicine sees through curve, calculating accumulation in 24 hours enters the medication amount of receiver media or accumulates through percentage rate through unit are skin.Can characterize the quality of the drug percutaneous permeability of different preparations according to the data obtained.
Fig. 2 is with after the penetrating promoter pretreatment of different percutaneous isolated rat skin of abdomen, accumulation transit dose (Q)～time (t) curve of Cucurbitacin B saturated solution Chinese medicine.As seen from Figure 2, oleic acid, azone, Oleum Eucalypti, isopropyl myristate, N-Methyl pyrrolidone, Mentholum, Borneolum Syntheticum, diethylene glycol monoethyl ether and propylene glycol have certain penetrating effect of promotion drug percutaneous, and wherein the penetrating facilitation effect of the percutaneous to Cucurbitacin B of oleic acid, azone, Oleum Eucalypti and isopropyl myristate is relatively good.Because cucurbitacin-type active ingredient has similar chemical constitution and physicochemical property, according to well known to a person skilled in the art principle, oleic acid, azone, Oleum Eucalypti and isopropyl myristate should have the penetrating facilitation effect of good percutaneous equally to other cucurbitacine active ingredients.
Fig. 3 be Cucurbitacin B gel through accumulation medicine transit dose (the Q)～time of different animals and different parts isolated skin (t) curve, Cucurbitacin B gel is prepared according to the prescription 3 in table 1.Curvilinear trend by Fig. 2 can be found out, Cucurbitacin B gel is through the certain time lag of the penetrating general existence of animal isolated skin, be only have at the initial stage a small amount of or do not have medicine to see through, then enter the stable stage that sees through, may there is decline to a certain degree in later stage transmission rates, penetrating stable of drug percutaneous sees through the persistent period in stage and can reach more than 24 hours.Permeability and the application on human skin of Corii Sus domestica to medicine is more approaching, and therefore, this result shows that it is feasible that cucurbitacin-type active ingredient percutaneous dosing obtains the people's vivo medicine concentration that is suitable for clinical treatment.
embodiment 2: oleic acid is the Cucurbitacin B gel of the penetrating promoter of percutaneous
Use the oleic acid of different amounts to prepare Cucurbitacin B gel as the penetrating promoter of percutaneous, prescription is in table 1, and preparation method is as follows: carbomer is fully swelling with part water, add appropriate triethanolamine adjust pH to 6-7, add 1,2-PD, fully stir, form sticky gel-type vehicle; By a small amount of water dissolution of EDTA-Na2, join in above-mentioned gel-type vehicle, fully stir; Ethanol is joined in gel, stir, then add the oleic acid of recipe quantity as the penetrating promoter of percutaneous and appropriate stabilizing agent, add water to recipe quantity, fully stir; Under lasting stirring, Cucurbitacin B powder is joined in above-mentioned gel-type vehicle, be stirred to medicine dissolution.
The prescription of Cucurbitacin B gel when the penetrating promoter of table 1. percutaneous is oleic acid and through the penetrating amount of accumulating for 24 hours of skin of rat
The gel making by above-mentioned prescription and technique is water white transparency or translucent, micro-ly has a milky sticky gel, has alcohol taste.This embodiment as gel matrix material, can hold ethanol and the propylene glycol of high-load with carbomer in prescription, ethanol and propylene glycol can dissolved substances and promoted that drug percutaneous is penetrating.Containing the Cucurbitacin B gel of different amounts oleic acid and the Cucurbitacin B gel that do not contain oleic acid through 24 hours accumulation medicine transit doses of skin of rat in table 1, accumulation medicine transit dose (Q)～time (t) curve is shown in Fig. 4.Result of the test shows that the consumption of oleic acid has the penetrating amount of best drug percutaneous while being 1%.The gel of each prescription is all without obvious skin hypersensitivity and zest.
embodiment 3: azone is the Cucurbitacin B gel of the penetrating promoter of percutaneous
Use the azone of different amounts to prepare Cucurbitacin B gel as the penetrating promoter of percutaneous, prescription is in table 2, and except replacing oleic acid with azone, preparation method is with embodiment 2.
The prescription of the Cucurbitacin B gel that the penetrating promoter of table 2. percutaneous is azone and accumulate penetrating amount for 24 hours through skin of rat
The gel making by above-mentioned prescription and technique is water white transparency or translucent, micro-ly has a milky sticky gel, has alcohol taste.Through 24 hours accumulation medicine transit doses of skin of rat, in table 2, result of the test shows that the consumption of azone has the penetrating amount of best percutaneous while being 1%.
embodiment 4: isopropyl myristate is the Cucurbitacin B gel of the penetrating promoter of percutaneous
Use the isopropyl myristate of different amounts to prepare Cucurbitacin B gel as the penetrating promoter of percutaneous, except replacing oleic acid with isopropyl myristate, preparation method is with embodiment 2.
The prescription of Cucurbitacin B gel when the penetrating promoter of table 3. percutaneous is isopropyl myristate and through skin of rat 24
Hour accumulate penetrating amount
The gel making by above-mentioned prescription and technique is water white transparency or translucent, micro-ly has a milky sticky gel, has alcohol taste.Through 24 hours accumulation medicine transit doses of skin of rat in table 3, result of the test shows that the consumption of isopropyl myristate increases, the penetrating amount of drug percutaneous increases, consider the factor such as saturation and skin irritation of gel to isopropyl myristate, the consumption of isopropyl myristate is more suitable in 10%.
embodiment 5: Oleum Eucalypti is the Cucurbitacin B gel of the penetrating promoter of percutaneous
Except replacing oleic acid with 1% Oleum Eucalypti, the prescription of Cucurbitacin B gel and preparation method are all identical with prescription 3 and preparation method in embodiment 2.
The gel making by above-mentioned prescription and technique is water white transparency or translucent, micro-ly has a milky sticky gel, has alcohol taste.Be 235.5 micro-gram per centimeters through 24 hours accumulation medicine transit doses of skin of rat
2.
embodiment 6: containing the gel of different cucurbitacin-type active ingredients
Prescription take Cucurbitacin B, cucurbitacin D, cucurbatacin E, cucurbitacin H, cucurbitacin I, cucurbitacin K or cucurbitacin Q as the gel of active component is in table 4, and the preparation method of gel is with embodiment 2.
Table 4. is containing the prescription of the gel of different cucurbitacin-type active ingredients and through the penetrating amount of accumulating for 24 hours of skin of rat
The gel making by above-mentioned prescription and technique is water white transparency or translucent, micro-ly has a milky sticky gel.In table 4, to different cucurbitacin-type active ingredients, all there is higher percutaneous transit dose through 24 hours accumulation medicine transit dose data of skin of rat.With hypromellose, as gel matrix material, solvent can be used the buffer salt solutions such as the citrate, tartrate, phosphate, acetate, borate of appropriate pH (5～8), and gel is more stable in preparation and storage process pH.The cellulose derivatives such as methylcellulose, alginic acid and salt thereof, polyvidone, poloxamer etc. also can be used as gel matrix material.N-Methyl pyrrolidone can be used as solvent, replaces part or all of ethanol or 1,2-PD in prescription, and wherein N-Methyl pyrrolidone has certain inhibition medicine hydrolysis.
embodiment 7: containing the gel of multiple cucurbitacin-type active ingredient
The gel that preparation contains multiple cucurbitacin-type active ingredient, wherein active component is each 0.2 gram of Cucurbitacin B and cucurbatacin E, and totally 0.4 gram, in prescription, other compositions are with writing out a prescription 1 in embodiment 6, and the preparation method of gel is with embodiment 2.The gel making by above-mentioned prescription and technique is light yellow translucent sticky gel, has alcohol taste.Cucurbitacin B and cucurbatacin E are respectively 210.39 micro-gram per centimeters through 24 hours accumulation transit doses of skin of rat
2with 168.62 micro-gram per centimeters
2.
embodiment 8: containing the patch of different cucurbitacin-type active ingredients
Adopt monolithic construction pressure sensitive adhesive patch, according to the prescription in table 5, take acrylate polymer as pressure sensitive adhesive matrix, plasticizer is triethyl citrate, acetone is that solvent is prepared patch, preparation method is as follows: by Cucurbitacin B, cucurbitacin D, cucurbatacin E, cucurbitacin I or cucurbitacin K acetone solution, add in the glue that contains pressure sensitive adhesive solution and the penetrating promoter of percutaneous, stir to obtain the glue of uniform and smooth, coating, dry, cover backing layer, cut into the patch of suitable area, the area of every subsides is 1-100 centimetre
2, generally with 2-20 centimetre
2be advisable.Make the suitable patch of viscosity by above-mentioned prescription and technique, through 24 hours accumulation medicine transit doses of skin of rat in table 5.
Except using triethyl citrate for plasticizer, also can adopt the medicinal plasticizers such as dimethyl phthalate, dibutyl sebacate, dioctyl phthalate.Pressure sensitive adhesive can be used the known medicinal pressure-sensitive adhesive materials such as acrylate, silicone rubber or polyisobutylene.Can use the volatile organic solvents such as acetone, ethanol, isopropyl alcohol, normal hexane, cyclohexane extraction, ethyl acetate or suitable mixed solvent to dissolve other compositions in pressure sensitive adhesive polymer and prescription.
Prescription composition and the medicine of table 5. cucurbitacin-type active ingredient patch are accumulated penetrating amount for 24 hours through skin of rat
embodiment 9: containing the patch of multiple cucurbitacin-type active ingredient
The patch that preparation contains multiple cucurbitacin-type active ingredient, wherein active component is each 0.2 gram of Cucurbitacin B and cucurbatacin E, and totally 0.4 gram, in prescription, other compositions are with writing out a prescription 4 in embodiment 8, and the preparation method of patch is with embodiment 8.The patch making by above-mentioned prescription and technique is micro-yellow, and viscosity is suitable.Cucurbitacin B and cucurbatacin E are respectively 128.0 micro-gram per centimeters through 24 hours accumulation transit doses of skin of rat
2with 112.5 micro-gram per centimeters
2.
embodiment 10: the ethosome of Cucurbitacin B or cucurbitacin D or cucurbatacin E
Prepare ethosome by following prescription and technique.Using Cucurbitacin B, cucurbatacin E or cucurbitacin D as active component, be dissolved in ethanol with soybean lecithin, under airtight, 50 ℃ of constant temperature, 700 revs/min of lasting stirring conditions, the distilled water of equitemperature is slowly injected with thread shape, stir 5 minutes, add the oleic acid of recipe quantity, mix homogeneously, is cooled to room temperature and get final product.
Composition consumption
0.2 gram of Cucurbitacin B, cucurbitacin D or cucurbatacin E
Phosphatidase 12 gram
30 grams of ethanol
1 gram of oleic acid
Distilled water adds to 100 grams
Cucurbitacin B ethosome is 375.44 micro-gram per centimeters through 24 hours penetrating amounts of medicine of skin of rat
2; Cucurbitacin D ethosome is 393.54 micro-gram per centimeters through 24 hours penetrating amounts of medicine of skin of rat
2; Cucurbatacin E ethosome is 398.27 micro-gram per centimeters through 24 hours accumulation medicine transit doses of skin of rat
2.
embodiment 11: Cucurbitacin B micro emulsion gel
Prepare Cucurbitacin B micro emulsion gel by following prescription and technique.Cucurbitacin B heating for dissolving, in oleic acid, adds Labraso/Cremophor RH40 mixture, and heating mix homogeneously, obtains concentrated microemulsion; Hypromellose is dissolved in the water of recipe quantity, adds above-mentioned concentrated microemulsion, is uniformly mixed, and to obtain final product.
Composition consumption
0.2 gram of Cucurbitacin B
6 grams of oleic acid
(1: 30 gram of Labraso/Cremophor RH40
1)
0.5 gram of hypromellose
Water to 100 gram
Cucurbitacin B microemulsion gel preparation is 219.6 micro-gram per centimeters through 24 hours accumulation medicine transit doses of skin of rat
2.
embodiment 12: Cucurbitacin B phospholipid organic gel agent (Lecithin Organogel)
Prepare Cucurbitacin B organic gel agent by following prescription and technique.Take phospholipid and isopropyl myristate, suitably add dissolving, add medicine and appropriate antioxidant, be stirred to after dissolving, add micro-water (in prescription, the ratio of the mole of water and the mole of phospholipid is about 3), stir, be cooled to room temperature, form the gelatin gel of thickness.In prescription, antioxidant can adopt the fat-soluble antioxidant that the medicaments such as vitamin E, BHA, BHT are conventional.
Composition consumption
0.05～2 gram of Cucurbitacin B
10～30 grams, phospholipid (phosphatidylcholine content is greater than 90%)
Antioxidant is appropriate
Water trace
Add isopropyl myristate to 100 gram
Cucurbitacin B phospholipid organic gel agent is (containing 0.02 gram of Cucurbitacin B, 8 grams of phosphatidase 11s, the mole of water is 3 with the ratio of the mole of phospholipid, isopropyl myristate to 100 gram) be 276.5 micro-gram per centimeters through 24 hours accumulation medicine transit doses of skin of rat
2.
embodiment 13: Cucurbitacin B solution and Cucurbitacin B spray
Prepare Cucurbitacin B solution by following prescription and technique.Take the composition in prescription, be dissolved in the mixed solvent of ethanol, 1,2-PD and water composition, to obtain final product.
Composition consumption
0.2 gram of Cucurbitacin B
30 grams of ethanol
20 grams of 1,2-PDs
1 gram of oleic acid
EDTA-Na
20.1 gram
Stabilizing agent is appropriate
Water to 100 gram
Cucurbitacin B solution is 436.2 micro-gram per centimeters through 24 hours accumulation medicine transit doses of skin of rat
2.
Above-mentioned solution is packed in suitable medicinal automiser spray, can make Cucurbitacin B spray.
Claims (6)
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| CN102133183B (en) * | 2011-03-04 | 2012-02-29 | 湘潭大学 | A kind of aciclovir ethosome and preparation method thereof |
| CN107149607A (en) * | 2017-06-01 | 2017-09-12 | 上海华堇生物技术有限责任公司 | Cucurbitacin H medicinal usage |
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